Contains 17 clinical situations of prolonged fever and discussion of various differential diagnosis based on them. Also gives the key points in the diagnosis of a prototype diagnosis and the usefulness of a relevant investigation modality in identifying these conditions. This power point presentaion is based on the chapter in Harrison's Text Book on Internal Medicine chapter on Fever of Unknown Origin

1. FEVER OF UNKNOWN ORIGIN Dr. S. Aswini Kumar. MD. Professor of Medicine, Medical College Hospital, Thiruvananthapuram.

2. Definition: Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in 1961 as temperatures higher than 38.3°C on several occasions, a duration of fever of more than 3 weeks, and failure to reach a diagnosis despite 1 week of in-patient investigation.

3. New classification: Durack and Street have proposed a new system for classification of FUO: classic FUO, nosocomial FUO, neutropenic FUO, and FUO associated with HIV infection

4. Classic PUO: This category corresponds closely to the earlier definition of FUO ,butthe new definition is broader, stipulating three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of "intelligent and invasive" ambulatory investigation.

5. 1. Diagnosis ? A 50 year old man was admitted with fever of three weeks duration. On examination there was hepatosplenomegaly. Routine urine and blood examinations were normal. Widal test and Mantouex test were negative. Chest X-Ray and HIV were negative. Liver biopsy showed presence of granulomas

6. Granulomatous hepatitis Systemic Sarcoidosis Miliary tuberculosis Lymphomas Wegener’s Brucellosis Histoplasmosis Shistosomiasis

7. Systemic Sarcoidosis

8. Liver Biopsy in FUO Mehngini/Vim’s/True cut needle To be cultured and retained

9. 2. Diagnosis? A 45 year old man was admitted to the CCU with acute MI, thrombolysed and reperfused, but then went into persistent hypotension following a cardiac arrest. He developed fever on Day 5. Routine blood investigation showed a polymorpho-nuclear leucocytosis. Blood culture was diagnostic

10. Nosocomial FUO: “In nosocomialFUO, a temperature of ³38.3°C develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. Three days of investigation, including at least 2 days' incubation of cultures, is the minimum requirement for this diagnosis”

11. Nosocomial FUO Post Myocardial infarction syndrome Pulmonary thromboembolism Occult Nosocomial infection Transfusion related viral infections Infected intra-vascular lines Catheter related infections Drug related fever

12. Blood Culture in FUO Method Rapid identification

13. Dressler’s Syndrome

14. 3. Diagnosis? A 30 year old farmer working in a diary farm in Tamil Nadu was admitted to the ward with low grade fever and evening rise of temperature. On examination there was generalized lymphadenopathy and hepato-splenomegaly. Blood routine, Chest X-ray PA view & Blood Widal test were negative

15. Systemic bacterial infections Brucellosis Typhoid fever Leptospirosis Campylobacter infection Meningococcemia Lyme’s disease Legionaire’s disease

16. Brucellosis

17. Serological Tests Widal Test Methodology

18. 4. Diagnosis? A 49 year old college Professor came with pain in the right loin and fever of one month duration. Loss of appetite and loss of weight were present. He was investigated for UTI. Repeated URE and urine cultures were negative. Renal angle was dull but non tender. CT scan of abdomen was diagnostic

19. Malignancies Renal cell carcinoma Pancreatic cancer Cancer colon Lymphoma Leukemia Hepatoma Sarcoma

20. Renal Cell carcinoma

21. Ultra-sound scan in FUO Look at USS Abd in RCC

22. 5. Diagnosis? A 14 year old boy was admitted with high grade fever and pallor. On examination no hepatosplenomegaly, lymphadenopathy or bone tenderness were present. The blood counts were as follows: Hb 8gm%, TC 3800, P8 L86 E4 M2, ESR 20 mm in 1st hr. Platelet count 2.5 lakhs, BT 1’30” CT 3’30”

23. Neutropenic FUO: NeutropenicFUO is defined as a temperature of 38.3°C on several occasions in a patient whose neutrophil count is <500/L or is expected to fall to that level in 1–2 days. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation, including at least 2 days' incubation of cultures

24. Neutropenic FUO Focal infections Systemic infections Bacterial infections Fungal infections Catheter infections Perianal infections Infections due to HSV and CMV

25. Cyclic Neutropenia

26. Bone Marrow studies Bone marrow aspiration Yields

27. 6. Diagnosis? A 55 year old woman presented with high grade remittent fever and severe pain in the right shoulder. No pallor/lymphadenopathy. Liver was palpable 8 cm below the costal margin. Soft and non tender. X ray chest and fluoroscopy showed elevated right hemi diaphragm with reduced movements

28. Pus somewhere Pancreatic abscess Pelvic inflammatory disease Prostatic abscess Tubo-ovarian abscess Sub diaphragmatic abscess Liver abscess Dental abscess

29. Pancreatic Abscess

30. CT Scan as a tool in FUO Pacreatic Abscess in CT Superior to USS Abd

31. 7. Diagnosis? A 19 year old girl was diagnosed to have infective endocarditis, because she had fever, pallor and systolic murmur. Repeated blood cultures were negative and she did not improve with antibiotics given for SBE. After 4 weeks she was skin and bones and still febrile. This time CXR was diagnostic

32. Tuberculosis Miliary tuberculosis Pulmonary Tuberculosis Tuberculous pleural effusion Tuberculous pericarditis Intestinal tuberculosis TB Lymphadenitis Renal tuberculosis

33. Miliary Tuberculosis

34. Chest X-Ray in FUO Diagnosis from CXR Encysted Empyema in CXR

35. 8. Diagnosis? A 25 year-old woman was admitted with a suspicion of rheumatic fever. A mid-diastolic murmur was audible to 4 out of 11 post graduate doctors in medicine who examined the case. ECG did not show RVH nor was there any straightening of the left border of heart in the chest X-ray PA view.

36. Cardiac Causes of FUO Left atrial myxoma Sub acute bacterial endocarditis Prosthetic valve endocarditis Aortic dissection Tuberculous pericardial effusion Chronic constrictive Pericarditis Post myocardial infarction syndrome

37. Left atrial myxoma

38. ECHO in FUO Diagnosis by ECHO Vegetation in ECHO

39. 9. Diagnosis? A 45 year old man , who returned from Mumbai where he was working as a taxi driver for the past twelve years. He was admitted with low grade fever and cervical lymphadenopathy. He was undergoing treatment from various hospitals for irritable bowel syndrome since last six months

40. HIV associated FUO: “HIV associated FUO is defined by a temperature of 38.3C (101F) on several occasions over a period of 4 weeks for outpatients or 3 days for hospitalized patients with HIV infection. This diagnosis is invoked if appropriate investigation over 3 days, including 2 days’ incubation of cultures, reveals no source.”

41. Human Inmmuno Deficiency HIV Infection as such Pulmonary Tuberculosis Pneumocystis Infection Toxoplasmosis Cytomegalovirus infection M. Avium or M. Intracellulare Non-Hodgkin’s Lymphoma

42. Toxoplasmosis

43. HIV testing in FUO IV Generation Screening CD4 counts and HIV RNA copies

44. 10. Diagnosis? A 15 year old boy was admitted with history of fever of seven days duration. Clinical examination showed a generalized maculopapular rash and generalized lymphadenopathy, hepatosplenomegaly. All the routine investigations for a underlying bacterial infection were found negative

45. Viral Infections Infectious Mononucleosis Hepatitis A B C D and E Ebstein Barr virus infection Cytomegalovirus infection Parvovirus infection Dengue hemorrhagic fever Lymphocytic chorio-meningitis

46. Cytomegalovirus infection

47. Virology in FUO Availability limitation H1N1 Serology

48. 11. Diagnosis? A sixty year old man was admitted with history of fever, headache and vomiting. O/E neck stiffness was present. Initial CSF study showed 50cells P60 L40. Repeat LP showed protein 45mg% and sugar 80mg%. Patient did not improve much in spite of combined regimen with antibiotics and ATT

49. Fungal Infections Cryptococcal meningitis Aspergillosis Blastomycosis Candidiasis Histoplasmosis Mucormycosis Sporotrichosis

50. Cryptococcal meningitis

51. CSF Study in FUO Highly informative Any time investigation

52. 12. Diagnosis? A 20 year-old college student ,while on an All India Tour on motor cycle , was involved in a road traffic accident and suffered from multiple fractures of the femur which necessitated multiple blood transfusions. He developed high grade fever with chills and rigor after one week

53. Parasitic Infections Malaria Amoebiasis Leishmaniasis P.carinii Toxoplasmosis Trichinosis Strongiloidiasis

54. Malaria

55. Peripheral Smear in FUO Simple bed side test Peripheral smear in Leukemia

56. 13. Diagnosis? A 14 year old girl was suffering from recurrent generalized seizures. She was put on Phenobarbitone and Dilantin sodium for the same. She had persistent low grade fever, but no lymph node enlargement or hepatosplenomegaly. Blood examination showed evidence of megaloblastic anemia

57. Drug fever/Non-infectious causes Gout Hematoma Haemolysis Cirrhosis of liver Pulmonary emboli Subacute thyroiditis Tissue infarction

58. Gout

59. Biochemical Tests in FUO Blood Chemistry Tests to be ordered

60. 14. Diagnosis? A 30 year old police man came with recurrent episodes of abdominal pain and abdominal distension, loss of weight and loss of appetite. He had fistulectomy on 2 occasions. He was weighing only 32kg. Pallor +. Abdomen was soft. No hepato-splenomegaly.Colonoscopy was diagnostic

61. Inflammatory Bowel Diseases Crohn’s disease Ulcerative colitis Intestinal tuberculosis Cholangitis Cholecystitis Mesenteric adenitis Osteomyelitis

62. Crohn’s disease

63. Tissue Biopsy in FUO Biopsy specimens Advantages & limitations

64. 15. Diagnosis? A 75 year-old man came with fever and headache of 4 months duration. He had generalized body aches and pains.He was admitted to ophthalmic hospital one week before for complaints of sudden loss of vision in one eye. Routine investigations were negative except for a high ESR

65. Connective tissue disorders Temporal arteritis Adult Still’s disease Systemic lupus erythematosus Rheumatoid arthritis Poly-arteritisnodosa Mixed connective tissue disease Relapsing polychondritis

66. Temporal arteritis

67. Collagen Work up in FUO ANA Profile Direct Immunoflourescence

68. 16. Diagnosis? A 45 year old lady came with generalized weakness, loss of weight and frequent loose stools. She always felt hot in her body and sweated excessively. Fine abnormal movements were present in the fingers. She had a fast heart rate which was out of proportion to her body temperature

69. Metabolic/endocrine disorders Hyperthyroidism Central causes Cerebrovascular accidents Encephalitis Brain tumor Hypothalamic dysfunction Pheochromocytoma

70. Hyperthyroidism

71. Endocrine Tests in FUO Array of tests Cover the system

72. 17. Diagnosis? A 19 year-old nursing student attending the OPD complained that she had high grade fever on several occasions in a day for past four weeks. She was unable to attend the ward examinations during this period because of the persistent fever. In between the fevers she was apparently healthy

73. Miscellaneous Disorders Factitious fever Habitual hyperthermia Afebrile FUO (<38.3oC) Exaggerated circadian rhythm Hysterical Fever MaliganantHyperthermia Neuroleptic Malignant Syndrome

74. Habitual hyperthermia

75. Conclusions

76. Thank You for the patient listening